Activity of the oral MEK inhibitor trametinib in patients with advanced melanoma: a phase 1 dose-escalation trial

Summary Background MEK is a member of the MAPK signalling cascade that is commonly activated in melanoma. Direct inhibition of MEK blocks cell proliferation and induces apoptosis. We aimed to analyse safety, efficacy, and genotyping data for the oral, small-molecule MEK inhibitor trametinib in patie...

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Published in:	The lancet oncology 2012-08, Vol.13 (8), p.782-789
Main Authors:	Falchook, Gerald S, Dr, Lewis, Karl D, MD, Infante, Jeffrey R, MD, Gordon, Michael S, MD, Vogelzang, Nicholas J, MD, DeMarini, Douglas J, PhD, Sun, Peng, PhD, Moy, Christopher, MS, Szabo, Stephen A, BA, Roadcap, Lori T, MS, Peddareddigari, Vijay GR, MD, Lebowitz, Peter F, MD, Le, Ngocdiep T, MD, Burris, Howard A, MD, Messersmith, Wells A, MD, O'Dwyer, Peter J, Prof, Kim, Kevin B, MD, Flaherty, Keith, MD, Bendell, Johanna C, MD, Gonzalez, Rene, Prof, Kurzrock, Razelle, Prof, Fecher, Leslie A, MD
Format:	Article
Language:	eng
Subjects:	Administration, Oral Adult Aged Antineoplastic Agents - administration & dosage Antineoplastic Agents - adverse effects Disease-Free Survival DNA Mutational Analysis Drug Administration Schedule Female Hematology, Oncology and Palliative Medicine Humans Kaplan-Meier Estimate Male MAP Kinase Kinase 1 - antagonists & inhibitors MAP Kinase Kinase 1 - metabolism MAP Kinase Kinase 2 - antagonists & inhibitors MAP Kinase Kinase 2 - metabolism Melanoma - drug therapy Melanoma - enzymology Melanoma - genetics Melanoma - mortality Melanoma - pathology Middle Aged Molecular Targeted Therapy Mutation Protein Kinase Inhibitors - administration & dosage Protein Kinase Inhibitors - adverse effects Proto-Oncogene Proteins B-raf - genetics Pyridones - administration & dosage Pyridones - adverse effects Pyrimidinones - administration & dosage Pyrimidinones - adverse effects Skin Neoplasms - drug therapy Skin Neoplasms - enzymology Skin Neoplasms - genetics Skin Neoplasms - mortality Skin Neoplasms - pathology Time Factors Treatment Outcome United States Uveal Neoplasms - drug therapy Uveal Neoplasms - enzymology Uveal Neoplasms - genetics Uveal Neoplasms - mortality Uveal Neoplasms - pathology Young Adult
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Summary:	Summary Background MEK is a member of the MAPK signalling cascade that is commonly activated in melanoma. Direct inhibition of MEK blocks cell proliferation and induces apoptosis. We aimed to analyse safety, efficacy, and genotyping data for the oral, small-molecule MEK inhibitor trametinib in patients with melanoma. Methods We undertook a multicentre, phase 1 three-part study (dose escalation, cohort expansion, and pharmacodynamic assessment). The main results of this study are reported elsewhere; here we present data relating to patients with melanoma. We obtained tumour samples to assess BRAF mutational status, and available tissues underwent exploratory genotyping analysis. Disease response was measured by Response Evaluation Criteria in Solid Tumors, and adverse events were defined by common toxicity criteria. This study is registered with ClinicalTrials.gov , number NCT00687622. Findings 97 patients with melanoma were enrolled, including 81 with cutaneous or unknown primary melanoma (36 BRAF mutant, 39 BRAF wild-type, six BRAF status unknown), and 16 with uveal melanoma. The most common treatment-related adverse events were rash or dermatitis acneiform (n=80; 82%) and diarrhoea (44; 45%), most of which were grade 2 or lower. No cutaneous squamous-cell carcinomas were recorded. Of 36 patients with BRAF mutations, 30 had not received a BRAF inhibitor before; two complete responses (both confirmed) and ten partial responses (eight confirmed) were noted in this subgroup (confirmed response rate, 33%). Median progression-free survival of this subgroup was 5·7 months (95% CI 4·0–7·4). Of the six patients who had received previous BRAF inhibition, one unconfirmed partial response was recorded. Of 39 patients with BRAF wild-type melanoma, four partial responses were confirmed (confirmed response rate, 10%). Interpretation Our data show substantial clinical activity of trametinib in melanoma and suggest that MEK is a valid therapeutic target. Differences in response rates according to mutations indicate the importance of mutational analyses in the future. Funding GlaxoSmithKline.
ISSN:	1470-2045 1474-5488